Rational Approach to Optimize Immune Potency of DNA Vaccines

Vaccines have provided the most cost-effective tool to control infectious diseases caused by viral and bacterial pathogens. However, there are no vaccines against any human parasitic infections and the development of an effective malaria vaccine remains an unachieved goal. Malaria infections account for nearly a million deaths out of ~ 300 million clinical cases globally on an annual basis.

Vaccines based on antigens targeting the sexual stages of the parasite provide a direct approach to reduce malaria transmission. Antibodies recognizing specific conformational epitopes in these proteins are potent blockers of infectivity of malaria parasites in the mosquito. In this R21 application we propose to assess cellular, molecular and immune correlates of efficacy and safety of modified DNA vaccines using a well characterized malaria vaccine candidate, Pfs25, as a model immunogen. DNA vaccines induce a good initial immune response;however, in larger mammals they require heterologous boosting, eg. adjuvanted proteins to sustain functional antibody titers.

Poor immunogenicity of DNA vaccines could result from an immune phenomenon described as T cell exhaustion or dysfunction resulting from upregulation of the programmed death 1 (PD-1) receptor in activated T cells and PD-L1 on antigen presenting cells. We propose to test this hypothesis through the novel addition of an RNAi sequence (designed to knockdown PD-L1) to a DNA vaccine and expect enhanced immunogenicity of DNA vaccines reflected in higher titer and longer lasting antibody responses.

These studies will provide a better understanding of the cellular and molecular correlates of immunogenic efficacy and safety of DNA vaccines, and also provide the basis for more in depth studies on vaccine development across a broad spectrum.

Project details

Immunology
Vaccines

Jun 2013 — May 2015

$393,000